Solutions, suspensions and emulsions have been used throughout the years as vehicles for delivery of the active ingredients of pharmaceutical drugs. These delivery vehicles do not allow for the maintenance of effective dosage levels of the active ingredients in the bloodstream. Sustaining a dosage of a therapeutic factor may require multiple injections, which can increase the likelihood of infection. Therapeutic factors such as pharmaceutical drugs and recombinant proteins often require controlled and sustained release at specific target tissues to be safe and effective. If there is a narrow difference between therapeutic and toxic levels (therapeutic index) of a drug it will require strict compliance to an injection schedule by the patient. Additionally, cytokines such as IL-2 have a danger of systemic toxicity. IL-2 has useful local therapeutic potential, but systemically it can cause vascular shock and pulmonary edema. Another concern is that therapeutic peptides have a very short half-life, so that targeted, controlled and sustained release is important for their effectiveness.
Recent advancements in the field of delivery vehicles allow for the controlled and sustained delivery of drugs. The advancements include such technologies as osmotic pumps, liposomes, dendrimers, and microencapsulation in biodegradable polymers such as microparticles, microspheres or nanoparticles. U.S. Pat. No. 4,489,055 to Couvreur et al., for example, describes biodegradable particles of alkyl-cyano-acrylate containing a biologically active substance. Particles comprised of various polymers and copolymers, such as PLG [poly(lactide-co-glycolide)], PCL [poly(,-caprolactone)], PLA [poly(L-lactic acid)] and PBLA [poly(.E-backward.-benzyl-L-aspartate)] have been described (M. Ravi Kumar J. Pharm. Parmaceut. Sci. 3(2): 234-258, 2000). Alginate (including calcium alginate beads encapsulated with poly-L-lysine) and chitosan have both been used extensively to create microcapsules and microspheres. Maintaining a minimal inflammatory response to the vehicle is important in any design for a delivery vehicle that is to be placed within the human body. Other advancements which allow for targeted and controlled release of factors include gene therapy. The use of a patient's own cells to carry the factor avoids some of the issues relating to immune rejection, since the drug vehicle is autologous.
One difficult tissue of the body to target with drugs or other factors is the synovium. Some have described the use of synovial fluid constituents for injection. For example, U.S. Pat. No. 4,141,973 to Balazs describe a purified high molecular weight hyaluronic acid fraction extracted from animal tissues for injection into a joint. U.S. Pat. No. 5,079,236 to Drizen et al. describe a purified high molecular weight hyaluronic acid fraction for treatment of joint disease in animals. HYALGAN sodium hyaluronate (Sanofi-Synthelabo Inc, New York, N.Y.) is a purified hyaluronate from rooster combs for injection into knee joints for the purpose of pain relief. U.S. Pat. No. 6,699,471 B2 and U.S. Patent Application Publication No. 2004/0142465 A1 to Radice et al. describe injectable compositions having hyaluronic acid derivatives and cells such as chondrocytes for the treatment of soft tissues. CARTICEL autologous cultured chondrocytes (Genzyme, Cambridge, Mass.) are presently used for the repair of articular cartilage defects caused by acute or repetitive trauma. The therapeutic chondrocytes are derived from an in vitro expansion of autologous chondrocytes harvested from the normal, femoral articular cartilage of the patient to be treated. The cells are isolated and expanded, then implanted into the articular cartilage defect beneath an autologous periosteal flap sutured over the cartilage defect.
The synovium and synovial fluid in patients with rheumatoid arthritis are known to have upregulated proinflammatory cytokines. Antiinflammatory agents are activated in the disease, but do not counter the proinflammatory response. Interferon-.E-backward. (IFN-.E-backward.) is a natural anti-inflammatory, because it downregulates proinflammatory cytokines such as IL-1.E-backward. and tumor necrosis factor-.A-inverted. (TNF-α while also increasing the IL-1 receptor antagonist in synoviocytes. Van Holten et al. (Arth. Res., vol. 6, no. 3) teach treatment in an animal model of rheumatoid arthritis using intraperitoneal injections of IFN-.E-backward. to ameliorate the arthritis. However, this requires systemic treatment with the IFN-.E-backward. Locally targeted therapy would be desirable. Bandara et al., Proc. Natl. Acad. Sci, USA, vol. 90, pp. 107641-10768 (1993) and Makarov et al., Proc. Natl. Acad, Sci, USA, vol. 93, pp. 402-406 (1996) take another approach by transducing synoviocytes with a cDNA so as to express the interleukin 1 receptor-antagonist (IL-1ra) protein. Del Vecchio et al. (Arth. Res., vol. 3, no. 4) teach approaches to enhance the transduction of human synoviocytes with the interleukin 1 receptor-antagonist (IL-1ra) cDNA. The ex vivo transfer of genes for delivering genes to the synovial lining of joints seems to selectively target type B synoviocytes. In vivo gene delivery by intra-articular injection of adenovirus vectors apparently transduces leukocytes and both type A and B synoviocytes (Evans, Arth, Res., vol. 1 no. 1, pp. 21-24, 1999). Research by Ghivizzani et al. (Proc Natl Acad Sci, USA 1998, 95:4613-4618) shows a contralateral effect of in vivo gene delivery, which suggests that transduced leukocytes have the capacity to traffic between joints.
While the related art teach various drug delivery vehicles which give controlled and sustained release, and while some related art utilize synovial fluid constituents such as hyaluronic acid for the treatment of joint disease, there still exists a need for improved delivery vehicles for factors, such as drugs, gene vectors and cytokines which allow for targeted, controlled and sustained release of the factors.